rs6040055

Variant names:

• chr20-10652665-T-C
• rs6040055
• NM_000214.3:c.756-67A>G

Your query was ambiguous. Multiple possible variants found:

• chr20-10652665-T-C
• chr20-10652665-T-A
• chr20-10652665-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000214.3(JAG1):​c.756-67A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 1,574,848 control chromosomes in the GnomAD database, including 306,720 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34321 hom., cov: 32)
  • Exomes 𝑓: 0.62 (272399 hom.)
• Consequence: JAG1 NM_000214.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.18
• Publications: 18 publications found

Genes affected

JAG1 (HGNC:6188): (jagged canonical Notch ligand 1) The jagged 1 protein encoded by JAG1 is the human homolog of the Drosophilia jagged protein. Human jagged 1 is the ligand for the receptor notch 1, the latter is involved in signaling processes. Mutations that alter the jagged 1 protein cause Alagille syndrome. Jagged 1 signalling through notch 1 has also been shown to play a role in hematopoiesis. [provided by RefSeq, Nov 2019]

JAG1 Gene-Disease associations (from GenCC):

• Alagille syndrome due to a JAG1 point mutation

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
• Charcot-Marie-Tooth disease, axonal, Type 2HH

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• tetralogy of fallot

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 20-10652665-T-C is Benign according to our data. Variant chr20-10652665-T-C is described in ClinVar as Benign. ClinVar VariationId is 1273216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000214.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	NM_000214.3	MANE Select	c.756-67A>G		intron	N/A	NP_000205.1	P78504-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	ENST00000254958.10	TSL:1 MANE Select	c.756-67A>G		intron	N/A	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.756-67A>G		intron	N/A	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.756-67A>G		intron	N/A	ENSP00000583797.1

Frequencies

GnomAD3 genomes AF: 0.666 AC: 101221 AN: 151970 Hom.: 34287 Cov.: 32

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.669

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.701

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.607

Gnomad OTH AF: 0.672

GnomAD4 exome AF: 0.617 AC: 877708 AN: 1422760 Hom.: 272399 Cov.: 22 AF XY: 0.619 AC XY: 439557 AN XY: 709770

African (AFR) AF: 0.809 AC: 26518 AN: 32780

American (AMR) AF: 0.694 AC: 30724 AN: 44256

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 16377 AN: 25732

East Asian (EAS) AF: 0.577 AC: 22657 AN: 39240

South Asian (SAS) AF: 0.700 AC: 59378 AN: 84782

European-Finnish (FIN) AF: 0.570 AC: 29045 AN: 50938

Middle Eastern (MID) AF: 0.650 AC: 3623 AN: 5570

European-Non Finnish (NFE) AF: 0.604 AC: 652664 AN: 1080522

Other (OTH) AF: 0.623 AC: 36722 AN: 58940

GnomAD4 genome AF: 0.666 AC: 101313 AN: 152088 Hom.: 34321 Cov.: 32 AF XY: 0.665 AC XY: 49460 AN XY: 74330

African (AFR) AF: 0.800 AC: 33215 AN: 41510

American (AMR) AF: 0.668 AC: 10208 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 2220 AN: 3468

East Asian (EAS) AF: 0.550 AC: 2827 AN: 5138

South Asian (SAS) AF: 0.699 AC: 3374 AN: 4824

European-Finnish (FIN) AF: 0.565 AC: 5972 AN: 10568

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.607 AC: 41275 AN: 67974

Other (OTH) AF: 0.671 AC: 1415 AN: 2110

Alfa AF: 0.631 Hom.: 90821

Bravo AF: 0.677

Asia WGS AF: 0.645 AC: 2247 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.10
DANN	Benign	0.34
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6040055; hg19: chr20-10633313; COSMIC: COSV54756150; COSMIC: COSV54756150;